The majority of pregnant women in malaria-endemic regions contract placental malaria (PM) at some point during gestation. PM is a severe form of malaria, leading to maternal complications and negatively affecting the survival and growth of the fetus. PM is defined as (1) the accumulation of Plasmodium falciparum-infected red blood cells (iRBCs) in the maternal blood spaces of the placenta, and (2) the cytoadherence of iRBCs to placental cells, such as syncytiotrophoblasts (STBs) that cover the chorionic villi and face the intervillous space where maternal blood circulates. One mechanism for iRBC cytoadherence to host receptors is through PfEMP1 proteins, encoded by parasite var genes and expressed on the surface of iRBCs in a mutually exclusive manner. With respect to placental receptors, chondroitin sulfate A (CS-A) has been consistently implicated in iRBC cytoadhesion. The physiological relevance of other purported receptors remains controversial, and most PM researchers agree that additional placental receptors remain to be described. Some gaps in knowledge remain. First, investigators have primarily focused on identifying receptors expressed by term placentas and have not considered the relationship between this tissue and iRBCs during early gestation. Second, they have only studied the involvement of the intervillous space in supporting cytoadhesion, completely ignoring the basal plate region of the placenta. Whether iRBCs cytoadhere to early gestation tissue and whether they cytoadhere to cells in the basal plate remain open questions that we are currently exploring with primary human placental tissue. We first reviewed the expression of putative receptors in early gestation tissue, both in the intervillous space and the basal plate. In the intervillous space, our results suggest that CS-A may not be involved in the initial stages of placental infection because we did not detect this antigen on the STB covering that is in contact with maternal blood. In the basal plate, our results reveal that cytotrophoblasts (CTBs) in contact with maternal blood express ICAM-1, a well-characterized receptor for iRBCs in non-pregnant individuals. We hypothesize that iRBC cytoadhesion may involve specific molecules that are uniquely expressed in both the intervillous space and the basal plate by early gestation human placental cells, including STBs and CTBs that are in direct contact with maternal blood. We will test this hypothesis with the following experiments. First (Aim 1), we will identify molecules that are spatially and temporally positioned to play a role in early gestation iRBC cytoadhesion. Next (Aim 2), we will functionally determine if these molecules act as early gestation placental receptors for iRBCs. Finally (Aim 3), we will identify cognate parasite-encoded ligands involved in cytoadhesion. At the conclusion of these experiments, we will have substantially advanced our understanding of the molecular interactions between iRBCs and the human placenta. Our proposed work will establish experimental systems for studying PM throughout human gestation and aid the malaria field in identifying potential drug and vaccine targets for treating this condition. PUBLIC HEALTH RELEVANCE: The results of the proposed experiments will substantially advance our understanding of the ligand-receptor molecular interactions between Plasmodium falciparum-infected red blood cells (iRBCs) and early gestation human placental tissue. As part of our proposed experiments, we will develop novel experimental models that will be useful to other researchers interested in studying placental malaria throughout human gestation. Our proposed work will realistically aid the malaria field in identifying potential drug and vaccine targets.